The cellular model of memory is a synaptic plasticity event called long-term potentiation (LTP). LTP can be divided into two phases: The early phase (E-LTP) lasts less than 2 hours and does not require new protein synthesis, and the late phase (L-LTP) can last many hours and requires new protein synthesis. Translation of mRNAs is regulated through various mechanisms, one of which is the binding of poly(A)-binding protein (PABP) to the poly(A) tail of the target mRNA. PAIP2A and PAIP2B (PAIP-interacting protein 2A and 2B) inhibit translation by interfering with PABP function. Khoutorsky et al. found that degradation of PAIP2A, which is the form that is abundant in the brain, linked synaptic activity to enhanced translation and contributed to learning and memory in mice. Hippocampal slices from Paip2a–/– mice showed L-LTP in response to a stimulus that only triggered E-LTP in slices from wild-type mice and showed impaired L-LTP in response to a stimulus that triggered L-LTP in slices from wild-type mice. Consistent with these electrophysiological studies, behavorial memory tests indicated that Paip2a–/– mice showed faster learning in spatial long-term memory tests in response to weak training but showed impaired learning in response to a long-term contextual fear conditioning test that used a strong training paradigm. Experiments with cultured neurons and hippocampal slices showed an activity-dependent decrease in the abundance of PAIP2A that could be prevented by pharmacological inhibition of the calcium-dependent proteases calpains. The calpain-dependent reduction in PAIP2A was also detected in mice subjected to the contextual fear conditioning paradigm, and infusion of calpain inhibitors impaired long-term contextual fear memory. Increased production of calcium-calmodulin kinase IIα (CaMKIIα) occurs in response to synaptic activity and is necessary for learning. The abundance of CaMKIIα in the hippocampus was increased in Paip2a–/– mice trained in a contextual fear conditioning paradigm compared with untrained mice or wild-type trained mice. This increase in CaMKIIα resulted from increased translation because CaMKIIα mRNA was shifted to heavy polysome fractions in the brains of Paip2a–/– trained mice and the association of PABP with this mRNA was greatest in the Paip2a–/– trained mice. Thus, activity-dependent degradation of a translation inhibitor contributes to the enhanced translation needed for learning and memory.